Early-stage hepatocellular carcinoma screening in patients with chronic hepatitis B in China: a cost–effectiveness analysis

Aim: To evaluate the cost–effectiveness of seven screening strategies for chronic hepatitis B (CHB) patients in China. Methods: A discrete event simulation model combining a decision tree and Markov structure was developed to simulate a CHB cohort aged ≥40 years on a lifetime horizon and evaluate the costs and health outcomes (quality-adjusted life years [QALYs] gained) of ultrasonography (US), alpha-fetoprotein (AFP), protein induced by vitamin K absence-II (PIVKA-II), AFP+US, AFP+PIVKA-II, GAAD (a diagnostic algorithm based on gender and age combined with results of AFP and PIVKA-II) and GAAD+US. Epidemiologic, clinical performance, utility and cost data were obtained from the literature, expert interviews and real-world data. Uncertainties on key parameters were explored through deterministic and probabilistic sensitivity analyses (DSA and PSA). Results: Compared with other strategies, GAAD+US detected the most HCC patients at early stage, and GAAD was the screening strategy with the lowest average cost per HCC case diagnosed. Using 3× China's 2022 GDP per capita ($38,233.34) as the threshold, the three strategies of US, GAAD and GAAD+US formed a cost–effectiveness frontier. Screening with US, GAAD, or GAAD+US was associated with costs of $6110.46, $7622.05 and $8636.32, and QALYs of 13.18, 13.48 and 13.52, respectively. The ICER of GAAD over US was $4993.39/QALY and the ICER of GAAD+US over GAAD was $26,691.45/QALY, which was less than 3× GDP per capita. Both DSA and PSA proved the stability of the results. Conclusion: GAAD+US was the most cost-effective strategy for early HCC diagnosis among CHB patients which could be considered as the liver cancer screening scheme for the high-risk population in China.

choice and is often applied beyond HCC surveillance to monitor other conditions, such as the development of portal hypertension, including the onset of ascites or portal vein thrombosis. 4 As per the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines, surveillance for HCC should be undertaken in high risk groups of patients and is recommended (B2).The combination of US and serum AFP measurement performed biannually should be used as a surveillance strategy for HCC. 5 Measurement of serum alpha1-fetoprotein (AFP) levels is a commonly used strategy for surveillance of HCC because it is widely available, inexpensive, and easy to perform.However, AFP has suboptimal performance as a serological test for surveillance of HCC because it depicts fluctuating levels in patients with cirrhosis with a flare of HCV or HBV infection, in exacerbations of the underlying liver disease, or with the occurrence of HCC.PIVKA-II is a precursor and abnormal form of prothrombin that is found in patients with HCC.This can be used to differentiate HCC from non-HCC hepatic diseases.Alternate name for PIVKA-II is des-gamma-carboxy prothrombin (DCP).The GAAD score can be easily calculated based on patient demographics and measurement of blood-based tumor markers using a small volume of blood draw.The GAAD score might be a practical, effective surveillance test where ultrasonography equipment and trained radiologists are scarce, which might improve compliance with surveillance and lead to improved effectiveness of cancer control programmes. 6he Elecsys GAAD test may be used in conjunction with diagnostic methods to detect early stage hepatocellular carcinoma.tubes or tubes containing separating gel and plasma samples collected in Li-heparin as well as Li-heparin plasma tubes containing separating gel.The Elecsys AFP and Elecsys PIVKA-II assays values must be determined from the same sample.Refer to the respective Method Sheet of the Elecsys AFP and Elecsys PIVKA-II assays for assay-specific information.

Calculation of the Elecsys GAAD test
The Elecsys GAAD test provides two interfaces to the users for the calculation of the Elecsys GAAD result.1. Graphical User Interface (Elecsys GAAD website)

Laboratory Information System (LIS)/Electronic Medical Records (EMR) Interface
The LIS/EMR Interface will enable Laboratories to automatically trigger the calculation of the Elecsys GAAD result.Through this interface, the Laboratories systems (LIS, EMR, Middleware) will be able to automatically send the following request data: ▪ Gender ▪ Age ▪ The Elecsys AFP assay value (for the range see section Calculation of the Elecsys GAAD using Elecsys assays, see also technical documentation) ▪ The Elecsys PIVKA-II assay value (for the range see section Calculation of the Elecsys GAAD using Elecsys assays, see also technical documentation) The Elecsys GAAD calculator will respond with the Elecsys GAAD score, result including the input values.

How to use the Elecsys GAAD calculator
1. Access the Elecsys GAAD calculator by typing www.elecsys-gaad.cominto your web browser.2.You will be redirected to the DiaLog portal to login.Login or create a new account.
3. After logging in on the DiaLog portal, you will be redirected back to the Elecsys GAAD website.4. A pop-up window appears with a "Terms of Service and Conditions of Use." Read the statement.Once the statement is understood, click on "I agree" to continue using the application.
Elecsys® GAAD is intended as an aid in diagnosis of early stage Hepatocellular Carcinoma (HCC).Elecsys® GAAD is indicated for adults who meet the following criteria: diagnosis of chronic liver disease and recommended for surveillance due to increased risk of developing HCC.Elecsys® GAAD must be interpreted in conjunction with other diagnostic findings and clinical information in accordance with standard clinical management guidelines.This is a placeholder text copied from the ROMA score.The text should include also the information of the use of Elecsys assays to calculate the Elecsys GALAD.By clicking "Agree" you (hereinafter "you" or "User") (i) agree to be legally bound to the following terms and conditions (the "Agreement") between you and F. Hoffmann-La Roche Ltd ("Roche"), (ii) confirm that you are a health care professional, and (iii) confirm that you are a non-US resident.

NO MEDICAL ADVICE
1.1.The Roche ROMA™ (Risk of Ovarian Malignancy Algorithm) calculator (the "Calculator") is for the calculation of patient's ROMA™ score using Elecsys® CA 125 II and HE4 immunoassays from Roche.
1.2.The Calculator is strictly to be used only in combination with test results from the Elecsys® CA 125 II and HE4 immunoassays from Roche.
1.3.The Calculator is developed for general educational purposes and for the use by health care professionals only.The results of the Calculator are not intended to be used for medical diagnosis or treatment.Health care professionals must exercise their own clinical judgment when using information derived from the Calculator.

5.
If "I agree" is chosen, the Elecsys GAAD calculator opens for use.6. Enter the correct gender, age and Elecsys AFP assay value and Elecsys PIVKA-II assay value into the appropriate input fields.For age and test result enter only numerical data.Valid ranges are displayed in grey text under each input field.If non-numerical data or data out of range is entered, the input field will be marked red as an alert to correct the associated data entry error (see section Calculation of the Elecsys GAAD test using Elecsys assays).

Calculator
Elecsys® AFP (ng/ml) 0.5 Input must be within range 2.72-1210 ng/ml.Test results outside this range are invalid.

Gender Age
Test results

Female Male
Age in years 4 Input must be within the values 18-150 years.

Intended use
Elecsys® GAAD is an in vitro diagnostic multivariate index assay intended to provide a semi-quantitative result by combining in an algorithm the quantitative measurements of Elecsys® AFP assay and Elecsys® PIVKA-II assay in human serum and plasma with gender and age.
Elecsys® GAAD is intended as an aid in diagnosis of early stage Hepatocellular Carcinoma (HCC).Elecsys® GAAD is indicated for adults who meet the following criteria: diagnosis of chronic liver disease and recommended for surveillance due to increased risk of developing HCC.Elecsys® GAAD must be interpreted in conjunction with other diagnostic findings and clinical information in accordance with standard clinical management guidelines.
7. Once the data inputs are correctly entered, click on the "Calculate" button beneath the input fields.8. Results from the calculations will be displayed in the results section of the screen: ▪ Inputs for gender, age, the Elecsys AFP and the Elecsys PIVKA-II assays will be verified and repeated.▪ Elecsys GAAD score from 0-10.▪ Positive/Negative Elecsys GAAD result.

Intended use
Elecsys® GAAD is an in vitro diagnostic multivariate index assay intended to provide a semi-quantitative result by combining in an algorithm the quantitative measurements of Elecsys® AFP assay and Elecsys® PIVKA-II assay in human serum and plasma with gender and age.
Elecsys® GAAD is intended as an aid in diagnosis of early stage Hepatocellular Carcinoma (HCC).Elecsys® GAAD is indicated for adults who meet the following criteria: diagnosis of chronic liver disease and recommended for surveillance due to increased risk of developing HCC.Elecsys® GAAD must be interpreted in conjunction with other diagnostic findings and clinical information in accordance with standard clinical management guidelines.

Result interpretation
The calculated Elecsys® GAAD score Z is evaluated with a predefined cutoff 2.57.If Z ≥ 2.57 then the Elecsys® GAAD result is positive, indicating a patient should be further evaluated by imaging and other HCC diagnostic testing.Elecsys® GAAD score (Z) increases with increasing risk of HCC.

Early detection in patients with chronic liver disease
The effectiveness of the Elecsys GAAD test as an aid in diagnosing of early stage HCC was determined in a prospective/retrospective, multi-center, case-control, observational study with HCC cases (confirmed diagnosis) and with control subjects (clinical diagnosis of cirrhosis of any etiology, noncirrhotic chronic HBV, non-cirrhotic chronic HCV and non-cirrhotic, non-alcoholic steatohepatitis (NASH).

Calculation of the Elecsys GAAD test using Elecsys assays
The Elecsys GAAD test is calculated based on gender (male or female), age in years and the results of Elecsys AFP and Elecsys PIVKA-II assays.Note: The equation used for the calculation of the Elecsys GAAD test uses values with the Elecsys AFP assay from 2.72-1210 ng/mL and with the Elecsys PIVKA-II assay from 4.5-12000 ng/mL.▪ If Elecsys AFP assay value is below or equal to 2.72 ng/mL, then input 2.72 ng/mL.▪ If Elecsys AFP assay value is above or equal to 1210 ng/mL, then input 1210 ng/mL.▪ If Elecsys PIVKA-II assay value is below or equal to 4.5 ng/mL, then input 4.5 ng/mL.▪ If Elecsys PIVKA-II assay value is above or equal to 12000 ng/mL, then input 12000 ng/mL.

Interpretation of Elecsys GAAD semi-quantitative test
The calculated Elecsys GAAD score Z is evaluated with a predefined cutoff 2.57.If Z ≥ 2.57 then the Elecsys GAAD result is positive, indicating a patient should be further evaluated by imaging and other HCC diagnostic testing.Elecsys GAAD score (Z) increases with increasing risk of HCC.

Clinical study for performance determination
To examine whether the Elecsys GAAD test provides additional information when used in combination with independent clinical or radiological evaluation a clinical study was performed.This study was a prospective, multi-center, blinded trial, which included 470 patients with chronic liver disease, where 364 patients met the inclusion criteria.Of the patients, 156 were diagnosed with HCC and 208 were found to be HCC free.The Elecsys GAAD test was determined using samples collected pre-diagnostic and values compared to the diagnoses are analyzed below:

Range of the Elecsys GAAD score in HCC cases compared to controls
The following table and graph show the range of the Elecsys GAAD score in samples from HCC patients staged according to the Barcelona clinic liver cancer classification (BCLC) compared to controls.
Elecsys GAAD Access to the Elecsys GAAD web calculator Materials required (but not provided) ▪ 04481798190, Elecsys AFP, 100 tests ▪ 04491742190, Elecsys AFP, 200 tests ▪ 07026706190, Elecsys AFP, 300 tests ▪ 08333602190, Elecsys PIVKA-II, 100 tests ▪ 08333629190, Elecsys PIVKA-II, 300 tests ▪ An internet-enabled device (PC, Tablet or Mobile) that has the most recent versions of Chrome, Safari, Edge and Firefox web browser installed on it Refer to the respective Method Sheet of the Elecsys AFP and Elecsys PIVKA-II assays for assay-specific required materials.
At the cutoff of 2.57, clinical performance of Elecsys® GAAD score in a multicentric validation cohort (156 HCC cases and 208 controls) is sensitivity of 78.9% for early stage HCC (BCLC stage 0 and A), sensitivity of 86.5% for all stage HCC (BCLC stage 0, A, B, C and D), and a specificity of 91.3% in cirrhotic or non-cirrhotic liver disease controls.For further information, please see the .or Download calculated results as needed.10.To continue using the Elecsys GAAD calculator, overwrite the input values with new data values as instructed in step 6 and continue through steps 7, 8 and 9. 11.To close the Elecsys GAAD website, click on the X in the web browser.12.To re-open and use the Elecsys GAAD calculator, go to Step 1.Limitations of the Elecsys GAAD testThe Elecsys GAAD test uses the combination of gender, age, Elecsys AFP and Elecsys PIVKA-II assay results.▪The Elecsys GAAD result cannot be used as absolute evidence for the presence or absence of malignant disease.▪ The Elecsys GAAD test should not be used as a standalone cancer screening test.▪ The Elecsys GAAD test has only been evaluated in adults ≥ 18 years of age with a diagnosis of chronic liver disease and under surveillance due to increased risk of developing HCC and is only intended for use in this population.▪ The Elecsys GAAD test should not be used without an independent clinical evaluation and is not intended to determine whether a patient should proceed to treatment.A negative Elecsys GAAD result, in the setting of a positive imaging examination should not preclude oncology referral.▪ The Elecsys GAAD test has not been validated for the following groups: adults previously treated for malignancy, adults currently being treated for malignancy and children < 18 years of age.The Elecsys AFP assay results should not be used interchangeably with other manufacturers' methods for AFP determinations in the Elecsys GAAD calculator.Use only the Elecsys AFP assay values obtained from Roche.The Elecsys PIVKA-II assay results should not be used interchangeably with other manufacturers' methods for PIVKA-II or DCP determination in the Elecsys GAAD calculator.Use only the Elecsys PIVKA-II assay values obtained from Roche.For the Elecsys AFP and Elecsys PIVKA-II assays input ranges see section Calculation of the Elecsys GAAD test using Elecsys assays.Values obtained from non-designated methods or a mix of instrument platforms may produce incorrect Elecsys GAAD results.An error in the calculation of results could lead to inaccurate likelihood of malignancy assessment and improper management of the patient.Refer to the respective Method Sheets of the Elecsys AFP and Elecsys PIVKA-II assays for assay-specific limitations and interferences.
> X: Control; O: State 0; A: State A; B: State B; C: State C; D: State D y --> Elecsys GAAD score The Elecsys GAAD score and disease etiology The following table and graph show the range of the Elecsys GAAD score in patient samples staged according to the etiology for both HCC cases (Label 1) and controls (Label 2).
8, 99.7)Cutoffs Receiver Operating Characteristic (ROC) for the Elecsys GAAD test and Elecsys AFP assay for early HCC Area Under the Curve (AUC) values (95 % CI) ): Elecsys AFP: 85.3 % (80.1 %-90.5 %), Elecsys GAAD: 92.9 % (89.4 %-96.4 %) Solid line: the Elecsys GAAD test, dashed line: the Elecsys AFP assay, long dashed line: angle bisector x --> specificity y --> sensitivity Number of all stage, early stage, late stage HCC cases, number of con trols, and the HCC fraction for given Elecsys GAAD score ranges Bar plot showing the fraction of all stage HCC cases within all sub jects for different Elecsys GAAD score ranges, with the corresponding error bars (95 % CI) > The Elecsys GAAD score ranges, [a;b) denotes an open interval (a ≤ x < b) and [a;b] a closed interval (a ≤ x ≤ b) y --> Proportion of all stage HCC within the Elecsys GAAD score ranges in %

Cutoffs of the Elecsys GAAD test for early HCC at specified sensitivity or specificity
The following tables show the clinical performance of the Elecsys GAAD test at different cutoffs for specified sensitivity or specificity on all stage HCC or controls.